HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Circ Res Manuscript Author . Author manuscript; Manuscript Author available in PMC 2018 September 15. Published in final edited form as: Circ Res. 2017 September 15; 121(7): 749–770. doi:10.1161/CIRCRESAHA.117.311059. Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy Ali J. Marian, M.D.* and Eugene Braunwald, M.D.† *Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, and Texas Heart Institute, Houston, TX †TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Abstract Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes, and a non-dilated left ventricle with preserved or increased ejection fraction. It is commonly asymmetric with the most severe hypertrophy involving the basal interventricular septum. Left ventricular outflow tract obstruction is present at rest in about one third of the patients, and can be provoked in another third. The histologic features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults. Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death. This complication can usually be averted by implantation of a cardioverter-defibrillator in appropriate high-risk patients. Atrial fibrillation is also a common complication and is not well tolerated. Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common genes involved, together accounting for about 50% of the HCM families. In approximately 40% of HCM patients the causal genes remain to be identified. Mutations in genes responsible for storage diseases also cause a phenotype resembling HCM (genocopy or phenocopy). The routine applications of genetic testing and preclinical identification of family members represents an important advance. The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents. SUBJECT TERMS GENETICS; CARDIOMYOPATHY Address for Correspondence: AJ Marian, M.D., Center for Cardiovascular Genetics, 6770 Bertner Street, Suite C900A, Houston, TX 77030, 713 500 2350, [email protected]. Marian and Braunwald Page 2 Author ManuscriptAuthor Keywords Manuscript Author Manuscript Author Manuscript Author Cardiac Hypertrophy; Genetics; human; Mutation; Sudden Cardiac Death; Heart Failure; Myosin heavy chain; Pathogenesis; cardiomyopathy; hypertrophic cardiomyopathy DEFINITION AND EPIDEMIOLOGY Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is characterized by cardiac hypertrophy, unexplained by the loading conditions, a non-dilated left ventricle and a normal or increased ejection fraction. Cardiac hypertrophy is usually asymmetric with greatest involvement most commonly of the basal interventricular septum subjacent to the aortic valve. It is occasionally restricted to other myocardial regions, such as the apex, the mid-portion as well as the posterior wall of the left ventricle. At the cellular level, cardiac myocytes are hypertrophied, disorganized, and separated by areas of interstitial fibrosis. HCM is a disorder without a distinct geographic, ethnic, or sex pattern of distribution. Prevalence of HCM has been estimated at 0.16% – 0.29% (~ 1:625 to 1:344 individuals) in the general adult population 1–4. In adults, HCM may be diagnosed by the presence of left ventricular end diastolic wall thickness > 13 mm on an echocardiogram or other imaging technique. 1 The European Society of Cardiology guidelines recommend using a left ventricular wall thickness of ≥ 15 mm in the diagnostic criteria. 5 Estimating the prevalence of HCM based on detection of cardiac hypertrophy, while clinically valuable, has a number of limitations. Notable among them is the age-dependent expression of cardiac hypertrophy; the latter is present in approximately one half of patients with the underlying causal mutations by the third decade of life and in approximately three fourths by the sixth decade. 6, 7. Given the age-dependent expression of HCM mutations, its prevalence is expected to be higher in older subjects. Indeed, HCM has been recognized in 0.29% (1:333) of 60-year old individuals undergoing echocardiography for cardiovascular evaluation in the U.S. 2. A similar prevalence has been reported in other parts of the world 3, 4. When more sensitive imaging methods are employed, when more family members are evaluated, and when genetic testing is more widely employed to them (see below), a much higher estimate of 0.6% (1:167) has been suggested 8–10. Cardiac hypertrophy may be of late onset, and less than 13 mm, the diagnostic cut point for the diagnosis of HCM 7, 11. Hence, HCM may be under-diagnosed in such individuals. Conversely, cardiac hypertrophy could result from the phenocopy conditions (see below), which might account for 5 to 10% of the clinically diagnosed HCM cases in children 12–14. Moreover, the presence of concomitant conditions which may cause myocardial hypertrophy, such as arterial hypertension or aortic stenosis, may make the differentiation of primary (HCM) from secondary hypertrophy challenging. However, the asymmetric shape of the ventricle with greatest hypertrophy of the basal interventricular septum and genetic testing of the subjects and their families (see below) may be helpful in this population. Circ Res. Author manuscript; available in PMC 2018 September 15. Marian and Braunwald Page 3 Author ManuscriptAuthor MOLECULAR Manuscript Author Manuscript Author GENETIC BASIS Manuscript Author HCM is an archetypical single gene disorder with an autosomal dominant pattern of inheritance 15, whereby a single mutation is usually sufficient to cause the disease, albeit with variable penetrance and expression. The variability of the phenotype is due, at least in part, to the causal mutation acting in concert with a number of other genetic and of non- genetic influences. Approximately 60% of patients with HCM have a clearly recognizable familial disease. Autosomal recessive and X-linked modes of inheritance have been described but are rare 16, 17. An X-linked inheritance typically raises the possibility of a phenocopy condition, such as Fabry disease 18. A phenocopy condition also occurs in syndromic conditions, such as the Noonan syndrome and in storage diseases, such as Anderson-Fabry disease. 18–20 The phenocopy (genocopy) conditions are not discussed. Pioneering studies by Christine and Jonathan Seidman have led to partial elucidation of the molecular genetic basis of HCM. The discovery of the p.Arg403Glu mutation in the MYH7 gene, encoding sarcomere protein β-myosin heavy chain (MYH7) in the French-Canadian family described by Paré et al, 21 paved the way for important subsequent discoveries. 22 The identification of multiple separate mutations in the principal causal genes, all encoding sarcomere proteins, (Figure 1), established HCM as a genetically heterogeneous disease. Among the known causal genes, MYH7 and myosin binding protein C (MYBPC3) are the two most common, together being responsible for approximately half of the patients with familial HCM 23–26. Mutations TNNT2, TNNI3, and TPM1 are relatively uncommon causes of HCM and together are responsible for less than 10% of cases 25–28. Mutations in ACTC1 (cardiac α-actin), MYL2 (myosin light chain 2), MYL3 (myosin light chain 3), and CSRP3 (Cysteine and Glycine Rich Protein 3) are also established, albeit uncommon, causes of HCM, 29–31. Evidence for the causal role of the above nine genes in HCM is the strongest (Table 1). 32, 33 Mutations in TTN (titin), TCAP (telethonin), MYOZ2 (myozenin 2), TRIM63 (ubiquitin E3 ligase tripartite motif protein 63 or MuRF1) and FHL1 (four and a half LIM domains 1) also have been implicated as causes of HCM, but occur typically in sporadic cases and small families 34–41. FHL1 is located on the X chromosome and mutations might affect hemizygous males disproportionately. Finally, mutations in TNNC1 (cardiac troponin C), MYH6 (myosin heavy chain or α-myosin heavy chain), PLN (phospholamban), CAV3 (caveolin 3), ALPK3 (α kinase 3), and JPH2 (junctophilin-2) have also been reported in patients with HCM 42–47, but their causal role in HCM is less certain and has not been established unambiguously (see below). A subset of pathogenic variants that exert large phenotypic effects, exhibit high penetrance, and co-segregate with the phenotype in large HCM families are considered the causal mutations 48–50. Causality of such mutations is robustly established through co-segregation and linkage analysis. This is the case for the common HCM genes, such as MYH7 and MYBPC3, whose causal role in HCM is unambiguous. Nevertheless, not all genetic variants in the established causal genes for HCM actually cause HCM 50.